Furo pyrimidin di-aromatic nucleus derivative epidermal growth factor inhibitor and preparation method and applications thereof

A technology of epidermal growth factor and pyrimidine, which is applied in the field of bisaromatic ring derivatives of furopyrimidine, can solve the problems of cancer recurrence in patients

Inactive Publication Date: 2019-11-01
YA THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, patients who develop secondary drug mutations to these drugs suffer from cancer recurrence within a few months

Method used

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  • Furo pyrimidin di-aromatic nucleus derivative epidermal growth factor inhibitor and preparation method and applications thereof
  • Furo pyrimidin di-aromatic nucleus derivative epidermal growth factor inhibitor and preparation method and applications thereof
  • Furo pyrimidin di-aromatic nucleus derivative epidermal growth factor inhibitor and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1: 2-{1'-N,N-dimethylaminoethyl-4'-acrylamido-7'-methoxy-1',2',3',4'-tetrahydro- 6'-quinoxaline}-4-(1"-methyl-1H-3"-indole)furo[2,3-D]pyrimidine (compound 401)

[0034]

[0035] Preparation of 2-chloro-4-(1'-methyl-1H-3'-indole)furo[2,3-D]pyrimidine:

[0036]

[0037] Dissolve 2,4-dichlorofuro[2,3-D]pyrimidine (0.75g, 4mmol) in ethylene glycol dimethyl ether (20mL), stir under ice bath, add ferric chloride (0.77 g, 4.59mmol), followed by stirring the reaction at room temperature for 15 minutes. Then N-methylindole (0.68 g, 5.2 mmol) was added dropwise, followed by heating to 60°C and stirring for 24 hours. Stop the reaction, lower to 0°C, add 3.5mL of methanol and 9mL of water, then stir the reaction at room temperature for 3 hours. A large amount of solid precipitated, filtered, washed the filter cake with methanol, and dried to obtain 0.82 g of yellow solid, yield: 72%. LC / MS (ESI): m / z 284 (M+H) + .

[0038] Preparation of tert-butyl 4-fluoro-2-me...

Embodiment 2

[0062] Example 2: 2-{1'-N,N-Dimethylaminoethyl-4'-acrylamido-7'-methoxy-1',2',3',4'-tetrahydro-6 '-quinoxaline}-4-(1"-methyl-4-aza-3"-indole)furo[3,2-D]pyrimidine (Compound 402)

[0063]

[0064] Preparation of 2-chloro-4-(1'-methyl-1H-3'-indole)furo[3,2-D]pyrimidine:

[0065]

[0066] Dissolve 2,4-dichlorofuro[3,2-D]pyrimidine (0.75g, 4mmol) in ethylene glycol dimethyl ether (20mL), stir under ice bath, add ferric chloride (0.77 g, 4.59 mmol), followed by stirring the reaction at room temperature for 15 minutes. Then N-methylindole (0.68 g, 5.2 mmol) was added dropwise, followed by heating to 60°C and stirring for 24 hours. Stop the reaction, lower to 0°C, add 3.5mL of methanol and 9mL of water, then stir the reaction at room temperature for 3 hours. A large amount of solid precipitated, filtered, washed the filter cake with methanol, and dried to obtain a yellow solid, 0.86 g, yield: 76%. LC / MS (ESI): m / z 284 (M+H) + .

[0067] 2-[1'-N,N-Dimethylaminoethyl-7'-metho...

Embodiment 3

[0073] Example 3: 2-{1'-N,N-dimethylaminoethyl-4'-butenamido-7'-methoxy-1',2',3',4'-tetrahydro- 6'-quinoxaline}-4-(3"-pyrazol[1,5-a]pyridine)furo[2,3-D]pyrimidine (Compound 403)

[0074]

[0075] 2-{1'-N,N-Dimethylaminoethyl-4'-acrylamido-7'-methoxy-1',2',3',4'-tetrahydro-6'-quinoxa Preparation of morpholine}-4-(3"-pyrazol[1,5-a]pyridine)furo[2,3-D]pyrimidine (compound 403):

[0076]

[0077] 2-[1'-N,N-Dimethylaminoethyl-7'-methoxy-1',2',3',4'-tetrahydro-6'-quinoxaline]-4-( 3"-pyrazolo[1,5-a]pyridine)furanopyrimidine (378mg, 0.76mmol) and DIPEA (0.146mL, 0.84mmol) were dissolved in dichloromethane (10mL), stirred at 0°C, and then dropped Add crotonoyl chloride (79mg, 0.76mmol) and dissolve in DCM (2mL) solution, then stir and react for 2 hours. The reaction is complete as detected by TLC. Stop the reaction, add DCM (50mL), then use 100mL saturated NaHCO 3 Washed with water, the aqueous layer was extracted with DCM (2*50mL), anhydrous MgSO 4 After drying and concentra...

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Abstract

The invention discloses a furo pyrimidin di-aromatic nucleus derivative epidermal growth factor inhibitor, and a preparation method and applications thereof, and more specifically discloses a selective inhibitor of clinical mutants of EGFR protein tyrosine kinase. The selective inhibitor possesses structures represented by formula I and II, and is a di-aromatic nucleus template compound containingfuro pyrimidin. The invention also discloses a preparation method of the compound, applications of the compound as a selective inhibitor on clinical mutants of EGFR protein tyrosine kinase, and especially the inhibition effect of the compound on T790M mutation epidermal growth factor EGFR, and applications of the compound in treatment of diseases, such as kidney cancer, lung cancer, prostate cancer, pancreas cancer, breast cancer, and gliocytoma, related with epidermal growth factor EGFR excess expression.

Description

technical field [0001] The present invention relates to furopyrimidine bisaromatic ring derivatives. Background technique [0002] Epithelial growth factor EGFR (epithelial growth factor receptor) is a 170kDa transmembrane glycoprotein receptor tyrosine kinase, which is activated by epidermal growth factor and affects cell growth and differentiation. Binding of EGF or TGF[alpha] to EGFR activates the receptor's tyrosine kinase activity. The tyrosine residues Tyr1068, Tyr1148, and Tyr1173 at the carboxy-terminus of EGFR are the major sites of autophosphorylation following EGF binding. Once activated, phosphorylated tyrosine residues at positions 1068 and 1173 of EGFR mediate the binding of Grb2 to EGFR. In addition, the phosphorylated tyrosine residue at position 1173 is the main binding site of SHC on EGFR. EGFR is widely distributed in many normal and malignant epithelial cells, and its overexpression and self-activation may be related to the occurrence and development o...

Claims

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Application Information

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IPC IPC(8): C07D491/048A61K31/519A61P35/00
CPCA61P35/00C07D491/048
Inventor 梁永宏曾兆森凌苑
Owner YA THERAPEUTICS INC
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